Erythropoietin Non-hematopoietic Tissue Response and Regulation of Metabolism During Diet Induced Obesity

Abstract

Erythropoietin (EPO) receptor (EPOR) determines EPO response. High level EPOR on erythroid progenitor cells gives rise to EPO regulated production of red blood cells. Animal models provide evidence for EPO activity in non-hematopoietic tissue mediated by EPOR expression. Beyond erythropoiesis, EPO activity includes neuroprotection in brain ischemia and trauma, endothelial nitric oxide production and cardioprotection, skeletal muscle wound healing, and context dependent bone remodeling affecting bone repair or bone loss. This review highlights examples of EPO protective activity in select non-hematopoietic tissue with emphasis on metabolic response mediated by EPOR expression in fat and brain and sex-specific regulation of fat mass and inflammation associated with diet induced obesity. Endogenous EPO maintains glucose and insulin tolerance and protects against fat mass accumulation and inflammation. Accompanying the increase in erythropoiesis with EPO treatment is improved glucose tolerance and insulin response. During high fat diet feeding, EPO also decreases fat mass accumulation in male mice. The increased white adipose tissue inflammation and macrophage infiltration associated with diet induced obesity are also reduced with EPO treatment with a shift toward an anti-inflammatory state and decreased inflammatory cytokine production. In female mice the protective effect of estrogen against obesity supersedes EPO regulation of fat mass and inflammation, and requires estrogen receptor alpha activity. In brain, EPOR expression in the hypothalamus localizes to proopiomelanocortin neurons in the arcuate nucleus that promotes a lean phenotype. EPO stimulation of proopiomelanocortin neurons increases STAT3 signaling and production of proopiomelanocortin. Cerebral EPO contributes to metabolic response, and elevated brain EPO reduces fat mass and hypothalamus inflammation during diet induced obesity in male mice without affecting EPO stimulated erythropoiesis. Ovariectomy abrogates the sex-specific metabolic response of brain EPO. The sex-dimorphic EPO metabolic response associated with fat mass accumulation and inflammation during diet induced obesity provide evidence for crosstalk between estrogen and EPO in their anti-obesity potential in female mice mediated in part via tissue specific response in brain and white adipose tissue. Endogenous and exogenous EPO response in non-hematopoietic tissue demonstrated in animal models suggests additional activity by which EPO treatment may affect human health beyond increased erythropoiesis.

Robust, Durable Gene Activation In Vivo via mRNA-Encoded Activators

“…To demonstrate that this approach can be generalized to other targets, we chose to upregulate the erythropoietin ( Epo ) gene. The encoded product, Epo, is a 34 kDa serum protein normally secreted by the kidney that regulates erythropoiesis in bone marrow. , Recombinant human Epo protein can be administered as a therapeutic in a variety of clinical scenarios, including chronic renal anemia, HIV infection, and oncologic disorders . Epo is also well-established for the evaluation of in vitro-transcribed mRNA performance, and its physiologic effects of increased red blood cell production can be easily measured from blood samples. ,, …”

“…To demonstrate that this approach can be applied to other genes with therapeutic applications, we chose the erythropoietin (Epo) gene as a second target. Epo is a protein hormone secreted by the kidneys that promotes erythropoiesis. , Recombinant forms of this protein are used clinically in scenarios such as chronic renal anemia …”

A New Target of Dental Pulp-Derived Stem Cell-Based Therapy on Recipient Bone Marrow Niche in Systemic Lupus Erythematosus

“…Some studies have reported that pharmacological treatment contributes to the de novo formation of the bone-like matrix and bone marrow-like niche of hBMMSCs. Erythropoietin (EPO) is a glycoprotein hormone produced in the kidney that stimulates red blood cell production [ 66 ]. Recent studies demonstrate that EPO can enhance the bone formation of osteoblasts [ 67 , 68 ].…”

“…The mechanism of hDPSC-EV secretion is currently unknown. RAB27A, a small GTPase, plays a vital role in regulating vesicle trafficking to secrete EVs from the parent cells at inflammatory sites [ 66 ]. A recent functional knockdown study showed that RAB27A could regulate the secretion of hDPSC-Evs from parental hDPSCs [ 35 ].…”

Pan-Cancer Analysis Based on EPOR Expression With Potential Value in Prognosis and Tumor Immunity in 33 Tumors

“…Activation of JAK2 results in the activation of specific downstream effectors, such as STAT1, STAT3, and STAT5 ( 4 ); the signal transducer and activator of transcription 5 (STAT5) usually refers to STAT5A and STAT5B proteins ( 5 ) and thus activates phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase 1/2 (ERK1/2) ( 6 , 7 ). EPOR was originally discovered and described in erythroid progenitor cells, but it is also present in non-hematopoietic cells (tissues, organs) such as adipose tissue ( 8 ), bone progenitor cells ( 9 ), neurons ( 10 ), endothelial cells ( 11 ), and intestinal tract ( 12 ). It is also widely present in various cancer cells and tumor tissues, such as head and neck squamous cell carcinoma (HNSC) ( 13 ), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC) ( 14 ), rhabdomyosarcoma ( 15 ), breast cancer ( 16 ), liver hepatocellular carcinoma (LIHC) ( 17 ), and laryngeal malignancy ( 18 ).…”